This web page was produced as an assignment for Genetics 677, an undergraduate course at UW-Madison.

Hemophilia A is..

Hemophilia A is an inherited bleeding disorder. Someone affected by Hemophilia A will bleed longer when becoming injured. Larger injuries can even cause those affected to have "bleeding episodes", where they cannot stop the bleeding for long periods of time. These bleeding episodes often cause bleeding into joints or muscles. The prevalence of the Hemophilia is about 1 in 5000 males in the United States [1].

Inheritance

Hemophilia A is an inherited X-linked recessive disorder that is caused by a defective gene on the X chromosome. This defect causes the factor VIII in the blood clotting process to malfunction, rendering the person incapable of clotting normally. Only one normal factor VIII gene on an X chromosome is needed to clot the blood normally. Women are more likely to not have Hemophilia A because they have two X chromosomes, and would need two defective factor VIII genes to have Hemophilia A. However, men only have one X chromosome, and that one X chromosome being defective, causes Hemophilia A. Although unaffected by Hemophilia, a woman with one mutated factor VIII gene is a carrier of the mutated gene. This means that she has a 50% chance of passing the mutated gene down to her children, giving males a 50% chance of having Hemophilia A, and females a 50% chance of being a carrier just like her mother, as shown in Figure 1. On the flip side, if a man with Hemophilia had children, all females would be carriers, and none of the males would be affected, also shown in Figure 1. Fortunately, prenatal intrauterine genetic testing is available for potential parents. [2]

Figure 1. X-linked Recessive Inheritance of Hemophilia A

Variable Expressivity

Hemophilia A has variable expressivity, so not every carrier or Hemophiliac will have the same symptom intensity. The intensity categories are normal, mild, moderate, and severe. Those with mild Hemophilia A usually only have between 6-49% of the clotting factor of a normal person. About 15% of the Hemophiliac population have moderate Hemophilia A, and only have 1-5% of the clotting factor carried in a normal person. Somewhere around 60% of Hemophiliacs have Severe Hemophilia A, and have less than 1% of the clotting factor in their blood [1].

Symptoms

Hemophilia A symptoms vary due to a wide variety of disease intensities.

Treatment

In order to treat Hemophilia A, one has to be diagnosed with it, or it has had to run in their family. Surprisingly, 30% of cases are found in people not known to have a family history of the disorder, and were actually caused by a random gene mutation [1]. If it is the first case found within the family, doctors will go about determining if they have it or not by using a variety of tests, called a coagulation study. Tests used include Low serum factor VIII activity, Low prothrombin time, Normal bleeding time, Normal fibrinogen level, and Prolonged partial thromboplastin time. Once diagnosis is confirmed, those with Hemophilia A can be treat injuries by replacing the missing clotting factor (by injection) with factor VIII concentrates. Mild Hemophilia A is treated with desmopressin, which helps the release of factor VIII from the lining of the blood vessels. For people with severe Hemophilia A, families can be taught to administer the factor VIII concentrates at home when needed. Many severe hemophiliacs develop inhibitors to factor VIII and need treatment with factor VIIa, which helps with clotting even if all factor VIII is gone. Despite the seriousness of Hemophilia A, most people are still able to lead almost normal lives with the correct treatment [2].

Coagulation Factor VIII Gene

Coagulation factor VIII gene resides on the long arm of the X chromosome.This is the gene that codes for the normal production of factor VIII clotting factor, that which is missing or reduced in those with Hemophilia A. There is an entire coagulation cascade involving many coagulation factors, which are all essential for normal clotting of the blood. Once the FVIII clotting factor protein is created in the liver, it circulates in the blood in an inactive state until an injury occurs. Once an injury occurs, the protein activates and interacts with other coagulation proteins to form a blood clot. When the factor VIII gene is mutated (depending on which mutation) it will cause either an abnormal factor VIII protein to be created, or reduce the number of factor VIII proteins available in one's body. This hinders the body's ability to form blood clots [4].